Yoshio Hoaki

Psychological stress enhances noradrenaline turnover in specific brain regions in rats

Concentrations of noradrenaline (NA) and 3-methoxy-4-hydroxyphenylethyleneglycol sulfate (MHPG-SO4) in the hypothalamus, amygdala, cerebral cortex and pons + medulla oblongata were examined in male Wistar rats exposed to foot-shock or to psychological stress for 1 hour. Animals in the psychological stress group were prevented from receiving foot shock, but were exposed to responses of shocked rats. Foot shocked rats exhibited a significant reduction in NA content and a significant elevation in MHPG-SO4 level in all brain regions when compared to control rats which were neither shocked nor exposed to shocked rats. Rats exposed to the psychological stress displayed a significant reduction of NA level in the amygdala, significant elevation of MHPG-SO4 content in the hypothalamus and amygdala, and a moderate elevation of plasma corticosterone level. These results suggest that psychological stress produces mild enhancement of NA release preferentially in the hypothalamus and amygdala; while foot shock stress elicits a more intense response of noradrenergic neurons in more extended brain regions.

Differential effects of morphine on noradrenaline release in brain regions of stressed and non-stressed rats

Effects of morphine on noradrenaline (NA) turnover in the 8 brain regions were investigated in non-stressed and stressed rats. Morphine at 3 mg/kg and 6 mg/kg caused dose-dependent increases in levels of 3-methoxy-4-hydroxyphenylethyleneglycol sulfate (MHPG-SO4), the major metabolite of brain NA, in the hypothalamus, amygdala, thalamus, hippocampus and midbrain and decreases in NA levels in the first 4 of these regions. In contrast to these enhancing effects of morphine on NA release in non-stressed rats, pretreatment with morphine at 6 mg/kg significantly attenuated immobilization-stress-induced increases in MHPG-SO4 levels in the above regions. The morphine effects in both states, non-stressed and stressed, were reversed by naloxone at 0.5 mg/kg and 5 mg/kg in the hypothalamus, amygdala and thalamus. These neurochemical changes are apparently related to the distress-evoked hyperemotionality. Behavioral changes observed during the restraint stress such as struggling, vocalization and defecation were attenuated by morphine at 6 mg/kg and enhanced by naloxone at 5 mg/kg, and this action of morphine was also reversed by naloxone at 5 mg/kg. These results suggest that morphine acts to attenuate stress-induced increases in NA release in the hypothalamus, amygdala and thalamus via opiate receptors, although the drug facilitates NA release in these regions in non-stressed rats. Together with previous findings that naloxone enhances stress-induced increases in NA release selectively in these regions, it is further suggested that endogenous opioids released during stress might act to inhibit NA release in these specific brain areas and that these decreased noradrenergic activities might be closely related to the relief of the distress-evoked hyperemotionality in animals.

Naloxene enhances stress-induced increases in noradrenaline turnover in specific brain regions in rats

Male Wistar rats were injected subcutaneously with either saline or naloxone, 1 mg/kg or 5 mg/kg, 10 min before exposure to 1-hour immobilization-stress. Control animals were sacrificed 70 min after respective injections. Levels of noradrenaline (NA) and its major metabolite, 3-methoxy-4-hydroxyphenylethyleneglycol sulfate (MHPG-S04) in seven discrete brain regions and plasma corticosterone levels were fluorometrically determined. Immobilization stress caused significant elevations of plasma corticosterone which were not affected by pretreatment with naloxone. In the hypothalamus, amygdala and thalamus, immobilization-stress caused significant elevations of MHPG-S04 levels, and naloxone at 5 mg/kg significantly enhanced these stress-induced elevations virtually without affecting the basal level of the metabolite. In contrast, in the hippocampus, cerebral cortex and pons plus medulla oblongata, MHPG-S04 levels were elevated by stress, but were not affected by naloxone pretreatment. The effect of naloxone on stress-induced reductions of NA levels was unclear, since naloxone by itself (5 mg/kg) significantly decreased the amine levels in 5 of 7 brain regions examined. These results indirectly suggest that endogenous opioid peptides in the hypothalamus, amygdala and thalamus are partly involved in the stress process and attenuate increases in NA turnover induced by stress.

Recovery of stress-induced increases in noradrenaline turnover is delayed in specific brain regions of old rats

Male Wistar rats at 2 and 12 months of age were sacrificed before, immediately following, and at 6 and 24 hours after a 3-hour immobilization stress period. Levels of noradrenaline (NA) and its major metabolite, 3-methoxy-4-hydroxyphenylethyleneglycol sulfate (MHPG-SO4), in eight brain regions and plasma corticosterone levels were fluorometrically determined. Immobilization stress caused significant increases of MHPG-SO4 levels in all brain regions examined and significant elevations in plasma corticosterone levels in both 2 and 12 month old rats. In 2 month old rats, the MHPG-SO4 levels in all brain regions returned to control levels within 6 hours after release from the stress. However, in 12 month old rats, the metabolite levels in the hypothalamus, amygdala, pons plus medulla oblongata (pons+med. obl .) and midbrain still remained at significantly increased levels at 6 and 24 hours after the stress. Moreover, in the amygdala of older rats, stress-induced decreases in NA levels persisted even 6 hours after stress. Plasma corticosterone levels also showed significant elevations at 6 and 24 hours after the stress only in 12 month old rats. These results suggest that brain NA metabolism during recovery periods from an acute exposure to a stressful situation is altered by the aging process in such a manner that NA neurons in the hypothalamus, amygdala, pons+med. obl . and midbrain in older rats remain activated by stressful stimuli for prolonged periods of time following release from stress.

Marked enhancement of noradrenaline turnover in extensive brain regions after activity-stress in rats.

Male Wistar rats were exposed to a 5-day activity-stress procedure wherein animals were housed in running-wheel activity cages and fed for only 1 hr each day (wheel-housed/food-restricted rats). This activity-stress procedure produced marked elevation in levels of the major metabolite of noradrenaline (NA), 3-methoxy-4-hydroxyphenylethyleneglycol sulfate (MHPG-SO4), in eight brain regions, while a reduction of NA level occurred in several of these brain regions. These rats also exhibited excessive running activity and developed severe gastric glandular ulcers. Rats fed ad lib and housed in activity cages (wheel-housed/ad lib-fed) and rats housed in standard-individual cages and which received either 1-hr daily feeding (control cage-housed/food-restricted) or ad lib feeding (control cage-housed/ad lib-fed) showed neither significant changes in brain NA metabolism nor gastric ulcers. These results suggest that the interaction of a restricted feeding regimen and an increase running wheel activity caused marked enhancement of NA turnover in several brain regions, which is one of the neurochemical mechanisms underlying the physiological and behavioral changes produced by the activity-stress paradigm.

Effects of age and stress on regional noradrenaline metabolism in the rat brain

Levels of noradrenaline (NA) and its major metabolite, 3-methoxy-4-hydroxyphenylethyleneglycol sulfate (MHPG-SO4), were determined in eight brain regions of non-stressed rats at 2, 10 and 15 months of age, and of rats at 2 and 15 months of age stressed by immobilization for 3 hours. The NA levels in older rats were significantly lower in the hypothalamus, pons + med.obl. and midbrain, and higher in the amygdala, thalamus, hippocampus and cerebral cortex as compared to those of 2 month old rats. The MHPG-SO4 levels in the older rats were significantly lower in the hypothalamus, amygdala, pons + med.obl. and midbrain, and higher only in the cerebral cortex than those in 2 month old rats. Immobilization stress caused significant increases in NA turnover in all brain regions of both 2 and 15 month old rats. Age-related difference in the degree of stress-induced change in NA metabolism was found only in the hypothalamus; the increase of MHPG-SO4 by stress was greater in 2 month old rats than in 15 month old rats, although both age groups of rats showed the same degree of NA reduction by stress. These data suggest that brain NA metabolism changes in an age-related fashion, and that apparent regional differences exist in the pattern of these changes. Specifically, it appears that there is an age-related difference in the response of noradrenergic neurons to stress in the hypothalamus.

Daily increase in noradrenaline turnover in brain regions of activity-stressed rats

Changes in contents of noradrenaline (NA) and its major metabolite, 3-methoxy-4-hydroxyphenylethyleneglycol sulfate (MHPG-SO4) in brain regions (the hypothalamus, amygdala, thalamus, hippocampus, midbrain, cerebral cortex, pons plus medulla oblongata and basal ganglia) of male Wistar rats were evaluated after 1, 3 or 5 days of exposure to the activity-stress paradigm, wherein rats were housed in a cage with a running-wheel and restricted to 1-hr of feeding per day. When compared to the non-stressed control rats, contents of MHPG-SO4 in all the brain regions except of the basal ganglia in the stressed rats increased as rapidly as 1 day and continued to increase throughout the 5-day activity-stress period. Contents of NA did not change significantly in most of these brain regions. The daily increase in regional NA turnover by continuous exposure to the activity-stress paradigm was related to the large increases in running activity and gastric ulcers, and to body weight loss at the 3-day and 5-day testing periods. These data suggest that pathological states produced by a 5-day activity-stress paradigm may reflect concomitant disturbances of noradrenergic function in various brain regions. The activity-stress paradigm is regarded as an intense and progressive stress, because it induces an increase in NA response in extended brain regions.

Prophylactic effect of neuroleptics in symptom-free schizophrenics: A comparative dose-response study of haloperidol and propericiazine

Remitted schizophrenic outpatients were treated in order to prevent relapse with three doses of haloperidol or propericiazine for 1 year in a double-blind controlled study employing a randomized design. The drugs ability to prevent relapse was evaluated by counting the number of symptom-free days for each patient before any sign of relapse or over-dose appeared. Patients were randomly assinged to the following drugs orally administered once per day at night: placebo; haloperidol 1 mg, 3 mg, and 6 mg; propericiazine 10 mg, 30 mg, and 60 mg. Serum prolactin levels in each patient were estimated by radioimmunoassay. All patients treated with placebo relapsed within 1 year and the relapse rate with placebo was significantly higher than with any dose of the two neuroleptics. Haloperidol increased the number of symptom-free days in a dose-dependent manner. Propericiazine at 10 mg and 30 mg also increased the number of symptom-free days dose-dependently but at 60 mg, the number decreased. It appears that propericiazine shows an inverted U-shaped dose-response curve. Prolactin levels were elevated dose-dependently by both drugs but failed to show a significant correlation with the number of symptom-free days. The present results indicate that haloperidol is superior to propericiazine from the viewpoint of the wider “therapeutic window” in maintenance treatment and antidopaminergic properties of neuroleptics, wherein it is important to prevent relapse even in remitted schizophrenics.

Influence of feeding situation on stomach ulcers and organ weights in rats in the activity-stress ulcer paradigm

Rats housed in running wheel activity cages except for 1 hr each day, during which time they were fed in their home cages, revealed more stomach ulceration, a higher level of brain MHPG-SO4, and larger weight changes in the thymus, spleen and adrenal gland, compared to rats housed in running-wheel activity cages and fed 1 hr daily in those same cages. Rats in the latter group showed more stress pathology than did control rats which were housed in standard home cages but which received the same restricted (1 hr per day) feeding schedule. These results did not support the idea that excessive running might occur in response to certain motivational states (e.g., frustration due to restricted feeding). The data suggested that feeding activity-stress rats in their home cages might aggravate the development of stomach ulcers coincident with the organ weight changes and the enhancement of noradrenaline turnover in the brain.

Differential modification by opioid agents of acutely enhanced noradrenaline release in discrete brain regions

Although immobilization stress-induced increases in MHPG-SO4 level in the hypothalamus, amygdala and thalamus were enhanced by naloxone and attenuated by morphine, both agents failed to exert significant effects upon regional MHPG-SO4 levels in methamphetamine-treated rats. The results indicate that there is a differential modification by opioid agents of acutely enhanced noradrenaline release induced by physiological and by pharmacological manipulations.